The objective of this application is to elucidate the mechanism of action of enkephalins and other endogenous opiod ligands. The investigation of the effects of these peptides on the noradrenergic, dopaminergic, serotonergic and cholinergic systems of the brain will comprise a major portion of our effort. We will also study the effects of these neurotransmitters on the synthesis and release of the peptides from rodent brain and AT t20 pituitary tumor cells in culture. A direct comparison will be made between the effects of a peptide which is resistent to rapid enzymatic degradation and has antinociceptive activity in rodents and methionine enkephalin which is devoid of antinociceptive activity and is rapidly metabolized. We propose to identify and characterize other endogenous substances which have opiate like activity in various in vitro and in vivo procedures.